Transforming growth factor beta secretion from primary breast cancer fibroblasts

Roozendaal, C.E.P. van; Klijn, Jan G.M.; Ooijen, B. Van; Claassen, C.; Eggermont, A. M. M.; Henzen‐Logmans, S. C.; Foekens, John A.

doi:10.1016/0303-7207(95)03539-j

Cited by 37 publications

(12 citation statements)

References 23 publications

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“…In addition, we report the expression of genes related to TGF-β by serum-activated fibroblasts. This finding is important because a number of previous studies have demonstrated that primary breast cancer fibroblasts secrete abundant TGF-β [25,26]. Finally, our immunocytochemical studies demonstrated that serum-activated fibroblasts uniformly express high levels of syndecan-1, a proteoglycan that is abundantly and specifically expressed by the stromal cells and myofibroblasts that are present in the connective tissue of human breast cancer [27,28].…”

Section: Discussionsupporting

confidence: 56%

Clonogenic growth of human breast cancer cells co-cultured in direct contact with serum-activated fibroblasts

2005

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IntroductionAccumulating evidence suggests that fibroblasts play a pivotal role in promoting the growth of breast cancer cells. The objective of the present study was to characterize and validate an in vitro model of the interaction between small numbers of human breast cancer cells and human fibroblasts.MethodsWe measured the clonogenic growth of small numbers of human breast cancer cells co-cultured in direct contact with serum-activated, normal human fibroblasts. Using DNA microarrays, we also characterized the gene expression profile of the serum-activated fibroblasts. In order to validate the in vivo relevance of our experiments, we then analyzed clinical samples of metastatic breast cancer for the presence of myofibroblasts expressing α-smooth muscle actin.ResultsClonogenic growth of human breast cancer cells obtained directly from in situ and invasive tumors was dramatically and consistently enhanced when the tumor cells were co-cultured in direct contact with serum-activated fibroblasts. This effect was abolished when the cells were co-cultured in transwells separated by permeable inserts. The fibroblasts in our experimental model exhibited a gene expression signature characteristic of 'serum response' (i.e. myofibroblasts). Immunostaining of human samples of metastatic breast cancer tissue confirmed that myofibroblasts are in direct contact with breast cancer cells.ConclusionSerum-activated fibroblasts promote the clonogenic growth of human breast cancer cells in vitro through a mechanism that involves direct physical contact between the cells. This model shares many important molecular and phenotypic similarities with the fibroblasts that are naturally found in breast cancers.

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Section: Discussionsupporting

confidence: 56%

Clonogenic growth of human breast cancer cells co-cultured in direct contact with serum-activated fibroblasts

2005

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“…Since it has been reported that FBS contains TGF-b and cells in culture secrete TGF-b [36,[48][49][50], the levels of latent and activated TGF-b were measured in basal media (BM) and CM. The concentration of TGF-b1 was below detectable levels in non-acidified samples of BM and CM collected from normal and CAF cultures treated with 0 ng/ml TGF-b1.…”

Section: Resultsmentioning

confidence: 99%

Cancer associated fibroblasts stimulated by transforming growth factor beta1 (TGF-β1) increase invasion rate of tumor cells: a population study

Casey

Eneman

Crocker

et al. 2007

Breast Cancer Res Treat

116

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Cancer associated fibroblasts (CAFs) are believed to promote tumor growth and progression. Our objective was to measure the effect of TGF-beta1 on fibroblasts isolated from invasive breast cancer patients. Fibroblasts were isolated from tissue obtained at surgery from patients with invasive breast cancer (CAF; n = 28) or normal reduction mammoplasty patients (normal; n = 10). Myofibroblast activation was measured by counting cells immunostained for smooth muscle alpha actin (ACTA2) in cultures +/- TGF-beta 1. Conditioned media (CM) was collected for invasion assays and RNA was isolated from cultures incubated in media +/- TGF-beta1 for 24 h. Q-PCR was used to measure expression of cyclin D1, fibronectin, laminin, collagen I, urokinase, stromelysin-1, and ACTA2 genes. Invasion rate was measured in chambers plated with MDA-MB-231 cells and exposed to CM in the bottom chamber; the number of cells that invaded into the bottom chamber was counted. Wilcox Rank Sum tests were used to evaluate differences in CAFs and normal fibroblasts and the effect of TGF-beta 1. There was no difference in percent myofibroblasts or invasion rate between normal and CAF cultures. However, TGF-beta1 significantly increased the percent of myofibroblasts (P < 0.01) and invasion rate (P = 0.02) in CAF cultures. Stromelysin-1 expression was significantly higher in normal versus CAF cultures (P < 0.01). TGF-beta 1 significantly increased ACTA2 expression in both normal and CAF cultures (P < 0.01). Expression of fibronectin and laminin was significantly increased by TGF-beta in CAF cultures (P < 0.01). CAFs were measurably different from normal fibroblasts in response to TGF-beta 1, suggesting that TGF-beta stimulates changes in CAFs that foster tumor invasion.

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“…Later on, this approach was supported by the results of different preclinical studies that showed the additive biological (Huynh et al, 1994) and anti-tumour effects (Weckbecker et al, 1994;Bogden et al, 1995) of somatostatin analogues to endocrine therapy with tamoxifen or by surgical oophorectomy in hormone sensitive tumours in vivo. Meanwhile, tamoxifen appeared not only to act by blocking the growth stimulatory effects of oestrogens but also to modify growth factor secretion (Coletti et al, 1989;Pollak et al, 1990;Butta et al, 1992;Clarke et al, 1992;Kiang et al, 1992;Lonning et al, 1992;Reed et al, 1992;Huynh et al, 1994;Winston et al, 1994;Kopp et al, 1995;Van Roozendaal et al, 1995) and to suppress the GH/IGF-I axis (Malaab et al, 1992;Pollak et al, 1992;Tannenbaum et al, 1992) and prolactin secretion (Klijn et al, 1985;, Malaab et al, 1992. Tamoxifen and other antioestrogens can decrease plasma IGF-1-levels (Coletti et al, 1989;Pollak et al, 1990;Kiang et al, 1992;Lonning et al, 1992;Reed et al, 1992;Winston et al, 1994), but also can down-regulate IGF-I-R (Freiss et al, 1990) and can suppress IGF-1-induced breast cancer cell proliferation (Pratt et al, 1993).…”

Section: Anti-tumour Effectsmentioning

confidence: 99%

Feasibility, endocrine and anti-tumour effects of a triple endocrine therapy with tamoxifen, a somatostatin analogue and an antiprolactin in post-menopausal metastatic breast cancer: a randomized study with long-term follow-up

Bontenbal

Foekens²,

Lamberts³

et al. 1998

Br J Cancer

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Summary Suppression of the secretion of prolactin, growth hormone and insulin-like growth factor 1 (IGF-1) might be important in the growth regulation and treatment of breast cancer. Because oestrogens may counteract the anti-tumour effects of such treatment, the combination of an anti-oestrogen (tamoxifen), a somatostatin analogue (octreotide) and a potent anti-prolactin (CV 205-502) might be attractive. In this respect, we performed a first exploratory long-term study on the feasibility of combined treatment and possible clear differences in endocrine and anti-tumour effects during such combined treatment vs standard treatment with tamoxifen alone. Twenty-two post-menopausal patients with metastatic breast cancer (ER and/or PR positive or unknown) were randomized to receive either 40 mg of tamoxifen per day or the combination of 40 mg of tamoxifen plus 75 ig of CV 205-502 orally plus 3 x 0.2 mg of octreotide s.c. as first-line endocrine therapy. An objective response was found in 36% of the patients treated with tamoxifen alone and in 55% of the patients treated with combination therapy. Median time to progression was 33 weeks for patients treated with tamoxifen and 84 weeks for patients treated with combination therapy, but the numbers are too small for hard conclusions. There was no difference in overall post-relapse survival between the two treatment arms. With respect to the endocrine parameters, there was a significant decrease of plasma IGF-1 levels in both treatment arms, whereas during combined treatment plasma growth hormone tended to decrease and plasma prolactin levels were strongly suppressed; in some patients insulin and transforming growth factor a (TGF-a) decreased during the triple therapy. Although there was no significant difference in mean decrease of plasma IGF-1 levels between the two treatment arms, combined treatment resulted in a more uniform suppression of IGF-1. Therefore, the addition of a somatostatin analogue and an anti-prolactin may potentially enhance the efficacy of anti-oestrogens in the treatment of breast cancer owing to favourable endocrine and possible direct anti-tumour effects. Large phase IlIl trials using depot formulations (to increase the feasibility) of somatostatin analogues are warranted to demonstrate the potential extra beneficial anti-tumour effects of such combination therapy.

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Transforming growth factor beta secretion from primary breast cancer fibroblasts

Cited by 37 publications

References 23 publications

Clonogenic growth of human breast cancer cells co-cultured in direct contact with serum-activated fibroblasts

Clonogenic growth of human breast cancer cells co-cultured in direct contact with serum-activated fibroblasts

Cancer associated fibroblasts stimulated by transforming growth factor beta1 (TGF-β1) increase invasion rate of tumor cells: a population study

Feasibility, endocrine and anti-tumour effects of a triple endocrine therapy with tamoxifen, a somatostatin analogue and an antiprolactin in post-menopausal metastatic breast cancer: a randomized study with long-term follow-up

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